JP2020111600A - Method for predicting biokinetics of liquid pharmaceutical composition - Google Patents

Abstract

To provide methods for predicting the biokinetics of component 1 obtained when one or more liquid pharmaceutical compositions containing the medicinal component (component 1) are subcutaneously administered to a mammal, and superiority or inferiority thereof.SOLUTION: Provided is a method and the like for predicting biokinetics parameters of component 1 and/or superiority or inferiority thereof, which is obtained by subcutaneously administering each of the compositions to a mammal, based on the elution result of component 1 obtained by applying one or more liquid compositions containing component 1 to an ion exchange chromatography.SELECTED DRAWING: None

Description

The present invention relates to a method for predicting the pharmacokinetics of a liquid pharmaceutical composition and the like.

Although the absorption of a drug in humans becomes clear in clinical trials, it would be extremely beneficial if the absorbability of a drug in humans could be predicted in the drug search stage (Non-Patent Document 6).
.. Further, the biomolecule zeta potential is known to be one index of the degree of electrostatic interaction with a charged surface (Non-Patent Document 7).

JP-A-5-306235 JP, 2004-010511, A JP, 2007-186466, A Tokuyo 2001-525372 International Publication No. 2012/169435 Special table 2012-522059 gazette Japanese Patent Publication No. 2015-504087 JP-A-63-57527 JP-A-2-96533 Special table 2004-513069 gazette JP, 2005-213158, A International Publication No. 2011/139838 Japanese Patent Publication No. 2014-507484

56.5 μg package insert for subcutaneous injection of Teribon (registered trademark) (revised in November 2015 (6th edition, revision of precautions, etc.)) Forteo (registered trademark) Subcutaneous injection kit 600 μg Package insert (revised July 2014 (7th edition)) Sung et al., Journal of Biological Chemistry, (1991), Vol.266, No.5, pp.2831-2835. Takai et al., Peptide Chemistry 1979, (1980), pp.187-192 Merrifield, Advances In Enzymology, (1969), Vol.32, pp.221-296 “Importance of Pharmacokinetic Studies in Drug Development and Future Development”, Sumitomo Chemical II (26-34) Salgin et al., International Journal of Electrochemical Science, (2012), Vol.7, pp.12404-12414

An object of the present invention is to provide a method for predicting or evaluating the pharmacokinetics of component 1 obtained when a liquid composition containing a medicinal component (component 1) is subcutaneously administered to a mammal. Another object of the present invention is to provide a method for treating and preparing a liquid composition for improving the pharmacokinetic parameters obtained when a liquid composition containing the component 1 is subcutaneously administered to a mammal. Furthermore, it is to provide a liquid composition containing component 1, which exhibits excellent pharmacokinetic parameters when administered subcutaneously to a mammal. Further, it is to provide a method for reducing the absolute value of the zeta potential of the component 1 in a liquid composition containing the component 1 and a liquid composition containing the component 1 having a reduced absolute value of the zeta potential.

One aspect of the present invention is that each composition is subcutaneously administered to a mammal based on the elution result of the component 1 obtained by applying one or two or more liquid compositions containing the component 1 to ion exchange chromatography. It is a method for predicting the pharmacokinetic parameter of component 1 obtained by administration and/or its superiority or inferiority. By carrying out the present method, the pharmacokinetics of the composition can be predicted without carrying out a burdensome and costly test such as a test using a laboratory animal or a clinical test.

One embodiment of the present invention evaluates or screens each composition based on the elution result of the component 1 obtained by applying one or more liquid compositions containing the component 1 to ion exchange chromatography. Is the way. This method has a lower load and cost as compared with a test using an experimental animal or a clinical test, and can easily evaluate or select drug candidates and the like.

One aspect of the present invention is a method of treating or preparing a composition containing component 1 comprising the step of reducing the effective surface charge exhibited by component 1. Moreover, one aspect of the present invention is a method for treating or preparing a liquid composition containing the component 1, wherein the liquid composition does not contain a buffering agent. By carrying out these methods, the pharmacokinetic parameters of component 1 obtained by subcutaneously administering the same composition to a mammal can be improved, or a good composition can be prepared.

One aspect of the present invention is a liquid composition containing Component 1 having a reduced effective surface charge. Furthermore, one aspect of the present invention is a liquid composition containing no component and containing component 1. These compositions are excellent in the pharmacokinetic parameters of component 1 obtained by subcutaneously administering the same composition to a mammal.

One embodiment of the present invention is a method for reducing the absolute value of zeta potential of component 1 in a liquid composition containing component 1, a method for preparing a liquid composition in which the absolute value of zeta potential is reduced, and a method for preparing zeta potential. It is a liquid composition having a reduced absolute value. The present liquid composition is, for example, the component 1 in the solution.
It is considered to give important suggestions regarding the evaluation of the effect of zeta potential on the absorption and separation processes of.

That is, the present invention relates to the following.
[1]
A method of predicting a pharmacokinetic parameter of component 1, which is obtained by subcutaneously administering a liquid composition a containing a medicinal component (component 1) to a mammal, comprising the steps of:
(1) A step of contacting the liquid composition a with an ion exchange resin and collecting the eluate thereof;
(2) A step in which the buffer solution b is brought into contact with an ion exchange resin and a series of steps for collecting the eluate is used as a unit step, and the unit step is repeatedly performed once or twice or more;
(3) measuring component 1 in each of the collected eluates;
(4) Identify or estimate the eluate with the largest amount of component 1 in each of the collected eluates, and/or identify the total amount of each eluate that has been eluted until the maximum elution of component 1 is reached. Or the process of estimating.
[2]
The method according to [1] above, wherein the pharmacokinetic parameters are AUC (area under plasma-time curve) and/or absolute bioavailability.
[3]
The method according to [1] or [2] above, wherein the ion exchange resin is a cation exchange resin.
[4]
Any of [1] to [3] above, wherein the volume of the buffer solution b contacted with the ion exchange resin in (2) is the same as the volume of the liquid composition a contacted with the ion exchange resin in (1). The method described in.
[5]
The method according to any of [1] to [4] above, wherein the mammal is a human.
[6]
The method according to any one of [1] to [5] above, wherein the medicinal component (component 1) is teriparatide or a salt thereof.
[7]
Liquid composition a is a liquid composition containing 28.2 μg of component 1 as a single dose, the mammal is human, and the pharmacokinetic parameter is AUC (plasma concentration-area under the time curve). The prediction method according to [6] above, which further comprises the step (5);
(5) When the amount of the eluate eluted until the maximum elution of component 1 estimated in (4) (component 1 elution volume) is 0.8 to 1.2 (mL), the AUC is 390. ~ 560 (pg·hr/
mL), its subranges, or specific values in those ranges, and the component 1 elution volume is 1.2 (mL), the AUC is 230 to 280 (pg·hr/mL), Expected to be subranges, or specific values within those ranges, with component 1 elution volumes of 1.2
In the case of ~1.6 (mL), AUC is predicted to be 190 to 380 (pg·hr/mL), a partial range thereof, or a specific numerical value in those ranges.
[8]
The liquid composition a is a liquid composition containing 28.2 μg of the component 1 as a single dose, the mammal is a human, and the pharmacokinetic parameter is an absolute bioavailability,
Furthermore, the prediction method according to the above [6], which comprises the step (5);
(5) If the amount of eluate (component 1 elution volume) eluted until the maximum elution of component 1 estimated in (4) is 0.8 to 1.2 (mL), it is an absolute organism. Scientific utilization rate is 110-150
(%), its subranges, or specific values within those ranges, and when the elution volume of component 1 is 1.2 (mL), the absolute bioavailability is about 70 (%). When the elution volume of component 1 is 1.2 to 1.6 (mL), the absolute bioavailability is 60 to 100.
(%), the partial range, or a step of predicting a specific numerical value in those ranges.
[9]
Liquid composition 1, liquid composition 2, containing a medicinal component (component 1), including the following steps:
... A method of predicting the superiority or inferiority of the pharmacokinetic parameters of component 1 obtained by subcutaneously administering each of the liquid compositions n (where n is an integer of 2 or more) to a mammal;
(1) applying each of the liquid compositions to ion exchange chromatography by a column method to determine or estimate the elution time of component 1 and/or the amount of eluate of component 1;
(2) A liquid composition having a shorter or smaller amount of component 1 elution time or component 1 eluate has a better pharmacokinetic parameter of component 1 obtained by subcutaneously administering the same composition to a mammal,
The process of predicting.
[10]
Liquid composition 1, liquid composition 2, containing a medicinal component (component 1), including the following steps:
... A method of predicting the superiority or inferiority of the pharmacokinetic parameters of component 1 obtained by subcutaneously administering each of the liquid compositions n (where n is an integer of 2 or more) to a mammal;
(1) A step of applying each of the liquid compositions to ion exchange chromatography by a batch method to calculate a recovery rate (%) of component 1;
(2) A step of predicting that a liquid composition having a higher recovery rate (%) of component 1 has a better pharmacokinetic parameter of component 1 obtained by subcutaneously administering the same composition to a mammal.
[11]
The method according to the above [9] or [10], wherein the pharmacokinetic parameter is AUC (area under plasma-time curve) and/or absolute bioavailability.
[12]
The method according to any one of [9] to [11] above, wherein the ion exchange resin is a cation exchange resin.
[13]
The method according to any of [9] to [12] above, wherein the mammal is a human.
[14]
The method according to any of [9] to [13] above, wherein the medicinal component (component 1) is teriparatide or a salt thereof.
[15]
A method for predicting a pharmacokinetic parameter of component 1, which is obtained by subcutaneously administering a liquid composition a containing a medicinal component (component 1) to a mammal, which comprises the following steps:
(1) a step of suspending the liquid composition a and an ion exchange resin and collecting the supernatant thereof;
(2) A step of calculating the recovery rate (%) of the component 1.
[16]
The method according to the above [15], wherein the pharmacokinetic parameters are AUC (area under the plasma concentration-time curve) and/or absolute bioavailability.
[17]
The method according to [15] or [16] above, wherein the ion exchange resin is a cation exchange resin.
[18]
The method according to any of [15] to [17] above, wherein the mammal is a human.
[19]
The method according to any of [15] to [18] above, wherein the medicinal component (component 1) is teriparatide or a salt thereof.
[20]
Liquid composition a is a liquid composition containing 28.2 μg of component 1 as a single dose, the mammal is human, and the pharmacokinetic parameter is AUC (plasma concentration-area under the time curve). The prediction method according to [19] above, which further comprises the step (3);
(3) When the recovery rate is 80% or more, AUC is 390 to 560 (pg·hr/mL),
It is predicted that the partial range or a specific numerical value in those ranges, and the recovery rate is 40 to 80.
If less than %, the AUC is predicted to be 190-380 (pg·hr/mL), its subranges, or specific numbers in those ranges.
[21]
The liquid composition a is a liquid composition containing 28.2 μg of the component 1 as a single dose, the mammal is a human, and the pharmacokinetic parameter is an absolute bioavailability,
Furthermore, the prediction method according to the above [19], including the step (3);
(3) When the recovery rate is 80% or more, the absolute bioavailability is 110 to 150 (%),
It is predicted that the partial range or a specific numerical value in those ranges, and the recovery rate is 40 to 80.
If less than %, predicting the absolute bioavailability to be 60-100 (%), its subranges, or specific values within those ranges.
[22]
By a method for improving the bioavailability and/or AUC (area under plasma concentration-time curve) of component 1 obtained by subcutaneously administering a liquid composition containing teriparatide or a salt thereof (component 1) to a human A method comprising reducing the effective surface charge of component 1 of the same composition.
[23]
By a method for improving the bioavailability and/or AUC (area under plasma concentration-time curve) of component 1 obtained by subcutaneously administering a liquid composition containing teriparatide or a salt thereof (component 1) to a human The method is characterized in that the composition does not include a buffering agent.
[24]
A method for preparing a liquid composition for subcutaneous administration containing teriparatide or a salt thereof (component 1), which comprises a step of carrying out the method according to any one of [1] to [23] above.
[25]
A liquid pharmaceutical composition for human subcutaneous administration containing teriparatide or a salt thereof (component 1) (excluding a liquid pharmaceutical composition reconstituted from a freeze-dried composition), which has an effective surface charge of component 1. Is characterized in that the recovery rate of the component 1 obtained by applying cation exchange chromatography by a batch method satisfying all of the following conditions 1) to 3) is 50% or more. A liquid pharmaceutical composition for human subcutaneous administration;
Condition 1) The cation exchange resin used for cation exchange chromatography is a strongly acidic cation exchange resin;
Condition 2) The buffer used for washing and/or equilibration of the cation exchange resin used for cation exchange chromatography is PBS (pH 7.4);
Condition 3) The volume ratio of the liquid pharmaceutical composition for human subcutaneous administration to be brought into contact with the cation exchange resin used for cation exchange chromatography is 1:50 to 100.
[26]
The liquid pharmaceutical composition for subcutaneous administration to human according to the above [25], which has a pH of 4.2 or more.
[27]
Liquid composition containing teriparatide or a salt thereof (component 1), and one or more components (component 2) selected from the group consisting of L-methionine, sodium chloride, L-arginine or a salt thereof, and sucrose. And a liquid composition having a pH of 3.0 to 5.0.
[28]
Furthermore, the liquid composition according to the above [27], which further comprises an acetate buffer.
[29]
Component 1: The liquid composition according to the above [27] or [28], wherein the component 2 is 1:0.5 to 50 (mass ratio).
[30]
A liquid composition containing teriparatide or a salt thereof (component 1) under the condition of pH of 3.0 to 5.0, comprising L-methionine, sodium chloride, L-arginine or a salt thereof, and sucrose. A method for lowering the absolute value of the zeta potential of component 1, comprising the step of incorporating one or more components (component 2) selected from the group.

According to the present invention, it is possible to economically design or develop a good liquid composition containing a medicinal component.

Hereinafter, the present invention will be described in detail with reference to specific embodiments. However, the present invention is not limited to the following embodiments, and may be implemented in any form without departing from the spirit of the present invention.

1. Ingredient 1, liquid composition containing Ingredient 1:
(1) Medicinal component (component 1)
In the present invention, the medicinal component is not particularly limited, and may be a component effective for treatment, prevention, diagnosis, etc. for mammals including humans. The structure of the medicinal component is not particularly limited, and may be a low molecular weight compound, a peptide, an antibody, a nucleic acid compound, a polysaccharide or the like. As a medicinal component, PTH(1-84), a partial peptide of PTH(1-84) or an analog thereof, which is PT
A component having a physiological activity equivalent to or similar to H(1-84) is preferable, and teriparatide or a salt thereof is more preferable.

In the present invention, human PTH(1-34) is human PTH, which is a human parathyroid hormone.
In the amino acid sequence of (1-84), it is a peptide represented by a partial amino acid sequence consisting of the 1st to 34th amino acid residues as viewed from the N-terminal side.

In the present invention, teriparatide means free human PTH(1-34).
Teriparatide can also be in salt form. Teriparatide and 1 as teriparatide salt
And any salt formed with one or more volatile organic acids. When teriparatide and the volatile organic acid form a salt, the ratio of both is not particularly limited as long as the salt is formed. Acetic acid is preferred as the volatile organic acid. That is, as the teriparatide salt in the present invention, teriparatide acetate can be preferably exemplified.

Since teriparatide or its salt is a peptide, it has its isoelectric point (pI).
The pI can be measured by a method known per se (for example, a method using HPLC or electrophoresis). Generally, the pI of teriparatide or a salt thereof is known to be 8.3 to 8.4.

(2) Liquid composition containing component 1:
The solvent of the liquid composition may be an aqueous solvent or a non-aqueous solvent, but is preferably an aqueous solvent. The aqueous solvent is an inorganic salt/organic salt, a buffering agent, within a range not departing from the gist of the present invention.
It may contain various components such as additives. Such components include, for example, disaccharides (
Examples thereof include sucrose), inorganic salt hydrochlorides or sodium salts (eg sodium chloride), neutral amino acids (eg L-methionine), and sugar alcohols (eg D-mannitol). Preferred examples of the aqueous solvent include water for injection and physiological saline.

The liquid composition can be used, for example, for treatment, prevention, diagnosis and the like of mammals including humans.

The amount of component 1 contained in the liquid composition is not particularly limited. Component 1 is PTH (1-84)
, A partial peptide of PTH(1-84) or an analog thereof, and a component having a physiological activity equivalent to or similar to PTH(1-84) (eg, teriparatide or a salt thereof), the following are preferably exemplified. it can. That is, the lower limit is preferably 10 μg or more, and 20 μg or more,
It is more preferably 25 μg or more, 27 μg or more, and further preferably 28 μg or more. The upper limit is preferably 100 μg or less, 50 μg or less, 40 μg or less, 35 μg or less.
g or less, and more preferably 30 μg or less.

When the component 1 is teriparatide or a salt thereof, the content of the component 1 as teriparatide is preferably 28.2 μg or 29.2 μg. When the component 1 is teriparatide acetate, an amount in which the amount of acetic acid is added can be exemplified. In the case of teriparatide pentaacetic acid, the content of the component 1 as teriparatide acetate is preferably 30.3 μg or 31.3 μg. ..

The dose of Component 1 contained in the liquid composition per administration is not particularly limited. Ingredient 1
Is PTH(1-84), a partial peptide or analog of PTH(1-84),
In the case of a component having the same or similar physiological activity as 1-84) (eg, teriparatide or a salt thereof), the following can be preferably exemplified. That is, the lower limit is 25 μg or more, 27 μg or more,
More preferably, it is 28 μg or more. The upper limit is 35 μg or less, 30
It is more preferably not more than μg, further preferably not more than 29 μg.

When component 1 is teriparatide or a salt thereof, the dose of component 1 per administration is preferably 28.2 μg as teriparatide. In the case where the component 1 is teriparatide acetate, an amount in which the amount of acetic acid is added can be exemplified, and in the case of teriparatide pentaacetic acid, the dose per component of the component 1 as teriparatide acetate is 30.3 μg. preferable.

The concentration of component 1 contained in the liquid composition is not particularly limited. When component 1 is teriparatide or a salt thereof, the following can be preferably exemplified. That is, in terms of teriparatide, the lower limit is preferably 50 μg/mL or more, more preferably 70 μg/mL or more, 100 μg/mL or more, more than 100 μg/mL, 110 μg/mL or more, and further 120 μg/mL or more. preferable. In terms of teriparatide, the upper limit is preferably 500 μg/mL or less, more preferably 250 μg/mL or less, less than 250 μg/mL, 200 μg/mL or less, 180 μg/mL or less, and further 160 μg/mL or less. preferable. Among them, 141 μg/mL is the most preferable example.

A liquid composition containing teriparatide or a salt thereof can be prepared by a method known per se (
For example, the methods described in Non-Patent Documents 3 to 5).

When the liquid composition is a liquid pharmaceutical composition, its administration route and subject are not particularly limited,
A liquid pharmaceutical composition for subcutaneous administration is preferable, and a liquid pharmaceutical composition for human subcutaneous administration is more preferable. The method for producing the liquid pharmaceutical composition is not particularly limited, but it can be produced, for example, by dissolving each of the weighed raw materials in water for injection or the like and sterilizing the solution by filtration. Water for injection is generally understood as sterile purified water that is suitable for pyrogen (endotoxin) test, and water for injection produced by a distillation method is sometimes referred to as distilled water for injection.

2. Methods for predicting the pharmacokinetics of component 1 contained in the liquid composition and its superiority or inferiority:
According to one aspect of the present invention, each composition is subcutaneously administered to a mammal based on the elution result of the component 1 obtained by applying one or two or more liquid compositions containing the component 1 to ion exchange chromatography. A method for predicting the pharmacokinetic parameter of component 1 obtained by administration and/or its superiority or inferiority is provided.
Alternatively, in one aspect, the present invention evaluates each composition based on the elution result of Component 1 obtained by applying one or two or more liquid compositions containing Component 1 to ion exchange chromatography. Alternatively, a method for screening is provided.

(1) Chromatography:
In the present invention, the type of chromatography is not particularly limited, but a column method or a batch method is preferable. The column method is a method in which a sample is passed through a column packed with an ion exchange resin, and the batch method is a method in which a sample is brought into contact with an ion exchange resin that is not packed in a column, and then a solution and an ion exchange resin are used. Is a method of separating. The chromatography may be cation exchange chromatography or anion exchange chromatography, but is preferably cation exchange chromatography.

The selection method of cation exchange chromatography and anion exchange chromatography is not particularly limited, but, for example, when the component 1 is a peptide or protein, the pH of the buffer solution used for cation exchange chromatography does not change the pH of the subcutaneous tissue. Given that the mimicking 6-8 is preferred, cation exchange chromatography is preferably selected when the pH of the buffer used is lower than its pI, and the pH of the buffer used is lower than its pI. If high, it is preferable to choose anion exchange chromatography.

Further, for example, in the case where the component 1 is a peptide or protein, in consideration of the pH range in which the component 1 is stable, if the pI of the component 1 is larger than the upper limit of the stable pH range, cation exchange is performed. Chromatography is preferred, and anion exchange chromatography is preferred if the pI of component 1 is below the lower limit of its stable pH range.

Thus, when the component 1 is a peptide or protein, the cation exchanger and the anion exchanger are appropriately selected in consideration of the buffer used for chromatography, the pI of the component 1, the stable pH range of the component 1, and the like. You can choose.

(2) Ion exchange resin, column, and packing of ion exchange resin into the column:
The anion exchange resin may be a strongly basic anion exchange resin or a weakly basic anion exchange resin, and has, for example, a trimethylammonium group, a dimethylethanolammonium group, a primary or secondary amino group as a functional group. The matrix structure (carrier) may be a resin having a styrene type or an acrylic type. As the anion exchange resin, a strongly basic anion exchange resin can be preferably exemplified.

The cation exchange resin, even at strongly acidic cation exchange resin may be a weakly acidic cation exchange resins, for example, as a functional ^{_{group, -SO 3 -, -COO -,}} -N (CH 2 COO -) have a _2, etc. However, a resin having a styrene-based or agarose-based resin as a matrix structure (carrier) can be used. As the cation exchange resin, a strongly acidic cation exchange resin can be preferably mentioned.

When the cation exchange resin has —SO ₃ ^— (sulfonic acid) as a functional group, a sulfomethyl group (—CH ₂ —SO ₃ ^— ) or a sulfomethyl group is used as a specific functional group introduced into the matrix structure (carrier). propyl _{(-CH 2 -CH 2 -CH 2 -SO} 3 -) and preferred examples. As the styrene-based matrix structure (carrier), a granular polymer formed of a copolymer of styrene and divinylbenzene can be preferably exemplified.

The average particle diameter of the ion exchange resin is not particularly limited, but the lower limit can be, for example, 3 μm or more, and is preferably 30 μm or more. The upper limit can be, for example, 200 μm or less, and above all, 150 μm or less is preferable. The average particle size is particularly preferably 65 μm. The average pore diameter of the ion exchange resin is not particularly limited, but is preferably 1 to 200 nm.
00 nm is more preferable. The ion exchange resin may be porous or non-porous.
As the cation exchange resin, for example, TOYOPEARL ^{(registered trademark)} SP-650M (manufactured by Tosoh Corporation) can be preferably exemplified.

In the column method, the column used is not particularly limited. The method for packing the ion-exchange resin in the column is not particularly limited, and for example, the column may be packed with the ion-exchange resin in a procedure of, for example, washing and activating the ion-exchange resin and then packing the column in a slurry state. it can. Alternatively, it is possible to purchase and use a column called a pre-column pack, which is filled with an ion exchange resin.

The required dose of the ion exchange resin can be appropriately determined according to the composition and dose of the component 1-containing liquid composition to be subjected to chromatography, the effective exchange amount of the ion exchange resin, and the like. In the column method, the size of the column to be used can be appropriately determined based on the amount of ion exchange resin and the like.

(3) Liquid composition containing component 1 to be subjected to chromatography:
The component 1-containing liquid composition (sample) to be subjected to chromatography can be one or two or more kinds of component 1-containing liquid compositions. For example, a plurality of kinds of liquid pharmaceutical compositions containing component 1 having different concentrations, pH, various additives, etc. of component 1 may be subjected to chromatography. When two or more kinds of component 1-containing liquid compositions are subjected to chromatography, it is preferable that the respective compositions are separately subjected to chromatography.

(4) Application to chromatography:
As described above, the chromatography may be, for example, column chromatography (chromatography by a column method) or batch chromatography (chromatography by a batch method).

Before contacting or suspending the ion-exchange resin and the liquid composition containing the component 1, it is preferable to wash and/or equilibrate the ion-exchange resin with a buffer solution or the like. The buffer used for washing and/or equilibration is not particularly limited, but as a pH that mimics subcutaneous tissue, p of the same buffer is used.
H is preferably about 6-8. As the buffer solution, for example, phosphate buffered saline (
Phosphate buffered saline (PBS), phosphate buffer, HEPES (4-(2-hydroxyethyl
)-1-piperazineethanesulfonic acid) buffer, Tris-buffered saline
saline; TBS) or the like can be used. The concentration of the buffer solution is not particularly limited, but is 10 to 200
It can be in the mM range.

(4-1) Application to column chromatography:
When applying the component 1-containing liquid composition to column chromatography, for example, 1) equilibration of the ion exchange resin with a buffer solution, 2) contact between the ion exchange resin and the component 1-containing liquid composition, 3) elution 4) Measurement of the amount of component 1 and 5) Determination or estimation of the elution time of component 1/the amount of eluate of component 1 can be exemplified.

(4-1-1) Equilibration of ion exchange resin with buffer:
The buffer may be used to equilibrate the ion exchange resin by the methods described above.

(4-1-2) Contact between ion-exchange resin and component 1-containing liquid composition:
Before contacting the ion-exchange resin with the component 1-containing liquid composition, the component 1-containing liquid composition is dialyzed against the buffer used for equilibration of the ion-exchange resin to remove components and solvents other than component 1 in the composition. It is also possible to replace with a buffer solution. However, as described above, when subjecting a plurality of kinds of liquid pharmaceutical compositions containing component 1 having different concentrations, pHs, various additives, etc. of component 1 to chromatography, such replacement treatment may not be carried out. preferable. The volume ratio of the resin to be brought into contact with the composition is not particularly limited, but can be resin volume:composition volume=1:0.1 to 100, 1:0.5 to 50, 1:0.8 to 8 , 1:0.9 to 3, or 1:0.5 to 1 (that is, the liquid volume of the composition to be contacted can be from the half volume of the resin volume to the same volume). , 1:0.5, that is, the liquid amount of the composition to be contacted is most preferably half the resin volume.

(4-1-3) Elution:
After contacting the ion-exchange resin with the liquid composition containing component 1, a solution containing or not containing component 1 may elute. The elution buffer may be contacted with the ion exchange resin before or after its elution, after which the solution with or without component 1 may elute. The elution here may include all such elution modes.

The elution buffer may have the same composition as the buffer used for equilibrating the ion exchange resin or a different composition. In the process of elution, the composition and pH of the elution buffer can be changed gradually (gradient method) or stepwise (stepwise method). The elution buffer can be manually added to the ion exchange resin, or can be added to the ion exchange resin using a liquid feed pump.

The elution buffer solution can be continuously added to the ion exchange resin, and a series of steps such as contacting a predetermined amount of the elution buffer solution with the ion exchange resin and collecting the eluate solution once or twice.
The elution can be repeated more than once.

Here, the numerical value of the predetermined amount of the elution buffer is not particularly limited, but can be about 0.1 to 10 ml. The ratio of the capacity of the ion exchange resin to the predetermined amount of the elution buffer is not particularly limited, but can be 1:0.1-100, 1:0.5-50, 1:0.8.
-8, 1:0.9-3 is preferable, or 1:0.5-1 (that is, the amount of the elution buffer to be contacted is half the resin volume to the same volume). You can also, among other things,
Most preferably, the predetermined amount of 1:0.5, that is, the predetermined amount of the elution buffer to be contacted is half the volume of the ion exchange resin.

The amount of the elution buffer may be the same as or different from the volume of the component 1-containing liquid composition (sample) that is brought into contact with the ion exchange resin. As described above, when elution is performed by repeating a series of steps, such as contacting a predetermined amount of elution buffer with the ion exchange resin and collecting the eluate once or twice, elution of the predetermined amount The volume of the buffer solution for use is preferably the same as the volume of the liquid composition containing 1 component (sample).

The eluate can be collected by fractionating into a plurality of containers using a fraction collector, for example.

(4-1-4) Measurement of component 1:
The method for measuring the amount/concentration of component 1 contained in each recovered eluate is not particularly limited, and it can be measured by a method known per se such as a physiological activity measuring method, an absorptiometric method, an immunological measuring method.

(4-1-5) Determination or estimation of component 1 elution time/component 1 eluate amount (component 1 elution result):
The elution time of the component 1 can be the time that elapses until the elution time of the eluate that has passed through the column is zero and the peak of the component 1 (maximum amount/maximum concentration) elutes. For example, a system comprising a pump for sending a buffer solution, an injector for injecting a sample that is a liquid composition containing component 1, a column filled with an ion exchange resin, and a detector for detecting a component eluted from the column is provided. By utilizing in the present invention, the elution time of component 1 can be determined or estimated.

The amount of component 1 eluate can be specified or estimated as the total amount of the eluate eluted until the component 1 peak (maximum amount/maximum concentration) is eluted. For example, it may be specified or estimated as the total amount of the liquid volume of the liquid composition containing component 1 and the liquid volume of the elution buffer added to the column before the peak of component 1 (maximum amount/maximum concentration) is eluted. it can.

For example, a column filled with an ion exchange resin is equilibrated with PBS, then 1 mL of a liquid composition containing component 1 is added to the column and the eluate is collected (the first collected liquid is collected). ), and further, a series of steps in which 1 mL of PBS was dropped into the same column to collect the eluate was repeated 5 times (collecting the second to sixth collection solutions), and as a result, the amount of component 1 in each eluate was When it was determined or estimated that the largest eluate was the third recovered liquid, the eluent volume of component 1 was set to 3
It can be determined or estimated as mL.

Alternatively, in the above-mentioned example, when the volume per addition of the sample and PBS was reduced to 0.5 ml, 6 eluents having the largest amount of component 1 among the eluates that would be recovered were obtained. ~
If it is judged that it can be the 8th, 3-4 mL is used instead of setting the elution volume of component 1 to 3 mL.
Can also be determined or estimated with a certain width.

(4-2) Application to batch chromatography:
When applying the component 1-containing liquid composition to batch chromatography, for example, 1) equilibration of the cation exchange resin with a buffer solution, 2) suspension of the ion exchange resin and the component 1-containing liquid composition (sample) The procedures such as turbidity, 3) collection of supernatant, 4) measurement of component 1 amount, 5) calculation of component 1 recovery rate can be exemplified.

(4-2-1) Equilibration of ion exchange resin with buffer:
The ion exchange resin can be equilibrated by the method described above.

(4-2-2) Suspension of liquid composition containing ion exchange resin and component 1:
The method of suspension is not particularly limited, but it may be suspended by stirring with a hand or a shaker for a certain time (about 1 to 30 minutes). The volume ratio of the resin to be suspended and the composition is not particularly limited,
Resin dose: composition dose=1:1 to 200, which can be 1:20 to 150, 1:30
˜120, 1:40 to 110, 1:50 to 100, or 1:60 to 70 is preferable.

(4-2-3) Collection of supernatant:
The supernatant can be collected after waiting until the suspension is substantially separated into the resin and the solution. Alternatively, the suspension may be filtered to separate the resin and solution.

(4-2-4) Measurement of the amount of component 1 in the recovered liquid (elution result of component 1):
The amount of component 1 in the recovered liquid (elution result of component 1) can be measured by the above-described component 1 amount measurement method.

(4-2-5) Calculation of component 1 recovery rate (elution result of component 1):
Component 1 recovery refers to the liquid composition containing Component 1 applied to chromatography (ie,
When the amount of component 1 contained in the sample of the liquid composition containing component 1 suspended in the ion exchange resin) is a and the content of component 1 contained in the recovery liquid is b, (b/a)×100 (%)
Can be calculated.

(5) Prediction, evaluation, or screening based on the elution result of component 1:
A drug of component 1 obtained by subcutaneously administering each composition to a mammal based on the elution result of component 1 obtained by applying one or more kinds of liquid compositions containing component 1 to chromatography. Kinetic parameters and/or their superiority or inferiority may be predicted. Alternatively, each composition can be evaluated or screened based on the same elution result.

The elution results of the component 1 obtained by applying the liquid composition containing the component 1 to the chromatography include the elution time of the component 1, the amount of the eluate of the component 1, and the recovery rate of the component 1 described above.

The pharmacokinetic parameter is not particularly limited, but the time to reach the maximum plasma concentration (T _max )
, Maximum plasma concentration (C _max ), plasma concentration-time curve area (AUC), and bioavailability (%). The AUC is not particularly limited and includes, for example, AUC _inf (area under plasma concentration-time curve until infinite time), AUC _last (area under plasma concentration-time curve until final observation time), And AU obtained at one administration interval during repeated administration
Examples include Cτ (area under the plasma concentration-time curve from time zero to administration interval time τ).

The mammal is not particularly limited, and examples thereof include rat, monkey, and human, and among them, human is most preferable.

The specific method for predicting the pharmacokinetic parameter and its superiority or inferiority is not particularly limited, but here, an example of the predictive method based on the elution result of component 1 shown in the examples of the present application will be described. The test results of the examples are shown in Tables 1 to 3 below.

When referring to Tables 1 to 3 in the prediction, the pharmacokinetic parameter prediction as in the following example can be performed.

(5-1) Prediction example 1:
When the eluate volume of component 1 is 0.8 to 1.2 (mL), AUC is 390 to 560 (pg
-Hr/mL), its partial range, or a specific numerical value in those ranges, and when the eluent volume of component 1 is 1.2 (mL), AUC is 230 to 280 (pg-hr/mL).
), its subranges, or specific values within those ranges, and the component 1 eluate volume is 1.2 to 1.6 (mL), the AUC is 190 to 380 (pg·hr). /M
L), its subranges, or specific values within those ranges.

(5-2) Prediction example 2:
When the amount of the eluent of component 1 is 0.8 to 1.2 (mL), the absolute bioavailability is 110.
~150(%), its subranges, or specific values in those ranges, and when the eluent volume of component 1 is 1.2 (mL), the absolute bioavailability is about 70%. And the component 1 eluate volume is 1.2 to 1.6 (mL), the absolute bioavailability is 6
It is predicted to be 0 to 100%, its partial range, or a specific numerical value in those ranges.

(5-3) Prediction example 3:
When the recovery rate of component 1 is 80% or more, AUC is 390 to 560 (pg·hr/mL)
, Its subranges, or specific values within those ranges, and the recovery rate for component 1 is 4
If it is 0 to less than 80%, the AUC is predicted to be 190 to 380 pg·hr/mL), a subrange thereof, or a specific numerical value in those ranges.

(5-4) Prediction example 4:
Absolute bioavailability is 110-150 (%) when the recovery rate of component 1 is 80% or more
, Its subranges, or specific values within those ranges, and the recovery rate for component 1 is 4
Absolute bioavailability is predicted to be 60-100%, a subrange thereof, or a specific number within those ranges if it is less than 0-80%.

Further, a plurality of types of component 1-containing liquid compositions (liquid composition 1, liquid composition 2,...,
The superiority or inferiority of the pharmacokinetic parameters of the component 1 obtained by subcutaneously administering a liquid composition n (n is an integer of 2 or more) to a mammal, and the component 1 obtained by applying each composition to chromatography Can be predicted based on the elution results of

For example, a liquid composition having a shorter dissolution time of component 1 has a pharmacokinetic parameter of component 1 obtained by subcutaneously administering the same composition to a mammal (a liquid composition having a longer dissolution time of component 1 It can be expected to be superior (compared to the pharmacokinetic parameters of component 1 obtained by subcutaneous administration to animals).

Alternatively, for example, in a liquid composition having a smaller amount of component 1 eluate, the pharmacokinetic parameter of component 1 obtained by subcutaneously administering the same composition to a mammal is (Compared to the pharmacokinetic parameters of component 1 obtained by subcutaneously administering the composition to a mammal).

Alternatively, for example, a liquid composition having a higher recovery rate of component 1 has a pharmacokinetic parameter of component 1 obtained by subcutaneously administering the same composition to a mammal (a liquid composition having a lower recovery rate of component 1). (Compared to the pharmacokinetic parameters of component 1 obtained by subcutaneous administration to mammals).

If the pharmacokinetic parameter is the absolute bioavailability (%) of component 1, the composition with the higher numerical value will have a greater absolute bioavailability (%) than the composition with the lower numerical value. %
) Is excellent. When the pharmacokinetic parameter is AUC, the composition with a higher numerical value is superior in terms of AUC to the composition with a lower numerical value. As a result of such prediction, a plurality of component 1-containing liquid compositions (liquid composition 1, liquid composition 2,...
., the liquid composition expected to have the best pharmacokinetic parameters with respect to the liquid composition n (n is an integer of 2 or more), and the second best pharmacokinetic parameter Liquid composition predicted to be present,..., Liquid composition predicted to have the poorest pharmacokinetic parameters, predicted among n kinds of liquid compositions The superiority or inferiority of pharmacokinetic parameters can be determined.

3. Treatment of the composition to improve its pharmacokinetics/Preparation of the composition:
One aspect of the present invention provides a method of treating or preparing a liquid composition containing Component 1, comprising the step of reducing the effective surface charge exhibited by Component 1.

Moreover, one aspect of the present invention is a method for treating or preparing a liquid composition containing the component 1, wherein the liquid composition does not contain a buffering agent.

By carrying out these methods, the pharmacokinetic parameters of component 1 obtained by subcutaneously administering the same composition to a mammal can be improved, or a good composition can be prepared.

Further, one aspect of the present invention is a liquid composition containing Component 1, which has a reduced effective surface charge. Moreover, one aspect of the present invention is a liquid pharmaceutical composition containing component 1, which does not contain a buffering agent. These compositions have excellent pharmacokinetic parameters for component 1, which are obtained by subcutaneously administering them to mammals. By not including a buffer in the composition, the component 1 in the composition
The mechanism by which subcutaneous administration of is improved the pharmacokinetics is not clear, but due to its absence,
For example, a mechanism may be considered in which the dynamics are improved by reducing either or both of the effective surface charge of component 1 or the electrostatic interaction between component 1 and subcutaneous tissue.

(1) Effective surface charge of component 1:
Component 1 contains many kinds of ionic amino acid residues, and can have both positive and negative charges on the surface of the molecule. The effective surface charge exhibited by component 1 can be understood as the sum of the charges present on the surface of such molecules. Since the charge state of amino acids changes with pH, the effective surface charge of component 1 also changes with pH.

The effective surface charge of the component 1 can be measured by, for example, ion exchange chromatography or electrophoresis.

(2) Means for reducing the effective surface charge of component 1:
The means for reducing the effective surface charge of the component 1 is not particularly limited, but the effective surface charge is reduced by increasing the pH containing the component 1, for example. Although the range of pH is not particularly limited, it can be a means for adjusting the pH to 4.2 or more, 4.5 or more, or 4.6 or more, and is 8.0 or less, 7.0 or less, 6.0 or less. , 5.0 or less, or 4.7 or less.

(3) No buffer is included:
The type of buffering agent is not particularly limited here, and examples thereof include acetic acid, tartaric acid, lactic acid, citric acid, boric acid, phosphoric acid, carbonic acid and salts thereof. Even if a trace amount of the buffering agent is contained in the liquid pharmaceutical composition, the buffering agent is not contained in the liquid pharmaceutical composition if it is not possible to suppress pH fluctuation due to decomposition of component 1 over time. Can be considered.

(4) Example of embodiment of liquid pharmaceutical composition:
The liquid pharmaceutical composition according to the present invention is a liquid pharmaceutical composition for human subcutaneous administration containing component 1, wherein the effective surface charge of component 1 is obtained when cation exchange chromatography by a batch method is applied. A liquid pharmaceutical composition for human subcutaneous administration, which is characterized in that the recovery of component 1 is adjusted to 50% or more, more preferably 70% or more, and most preferably 80% or more. .. Here, the upper limit of the recovery rate of the component 1 is not particularly limited, but theoretically it is 100%.

The liquid pharmaceutical composition of the present invention may include an embodiment of a liquid pharmaceutical composition reconstituted from a lyophilized composition, and need not be a liquid pharmaceutical composition reconstituted from a lyophilized composition. That is, it may be a liquid pharmaceutical composition prepared by dissolving (re-dissolving) a lyophilized composition containing component 1 in physiological saline or the like at the time of use. It may be a liquid composition).

The component 1 is as described above, but here, teriparatide or a salt thereof is preferable. The resin used for cation exchange chromatography is also as described above, but here,
It is preferably a strongly acidic cation exchange resin. The buffer solution used for washing and/or equilibration of the ion exchange resin is also as described above, but phosphate buffered saline (PBS) is preferable here, and its pH is 7.4. preferable. The contact ratio (volume ratio) between the ion exchange resin and the liquid pharmaceutical preparation containing component 1 is preferably 1:50 to 100.

4. Methods for reducing the absolute value of zeta potential:
Zeta potential is understood as the surface charge of fine particles present in a solution, and more precisely is defined as the potential of a slip surface in an electric double layer formed around the fine particles present in a solution. .. Further, in general, colloids having a high zeta potential (negative or positive) are electrically stabilized, and colloids having a low zeta potential have weak repulsion forces with each other and, as a result, have a high tendency to aggregate.

One embodiment of the present invention is a method for reducing the absolute value of zeta potential of component 1 in a liquid composition containing component 1. This method makes it possible to prepare a liquid composition having a reduced absolute value of zeta potential. Then, the present liquid composition is considered to give important suggestions regarding, for example, the evaluation of the influence of the zeta potential on the absorption/separation process of the component 1 in the solution.

The zeta potential can be measured using a method or an apparatus known per se in the technical field, for example, by measuring the electrophoretic mobility of particles in a solution by light scattering electrophoresis (ELS) and then measuring the mobility. The zeta potential can be obtained by converting to the zeta potential (
Patent Document 6). As such a device, for example, the Zetasizer series of Malvern Co. can be mentioned.

Specifically, the method comprises at least at least one of a monosaccharide, a disaccharide, a sugar alcohol, an amino acid or a salt thereof, and an inorganic salt in a liquid composition containing the component 1 under conditions where the pH is acidic to neutral. It may be a method including a step of incorporating component 1 (component 2). As the component 2, for example, a combination of a disaccharide and an inorganic salt can be preferably exemplified.

Here, acidic means a state (pH) of less than pH 3.0, and neutral means 6.0 to 8.0.
Means a state (pH). The condition that the pH is acidic to neutral is not particularly limited as long as this is the case, but the lower limit of the pH can be 2.0 or more, 3.0 or more, 4.0 or more, 5.0 or more, Above all, it is preferably 4.0 or more. The upper limit of pH is 8
． It may be 0 or less, 7.0 or less, 6.0 or less, 5.0 or less, 4.5 or less, 4.0 or less, and among them, preferably 5.0 or less, and 4.5 or less. It is more preferable that there is.

Among the component 2, examples of monosaccharides include glucose, fructose and galactose,
Examples of disaccharides include sucrose, maltose, and lactose. The amino acid or salt is not particularly limited, but a neutral amino acid, a basic amino acid, or a salt thereof is preferably exemplified. Among the neutral amino acids, sulfur-containing amino acids are more preferable, and methionine (preferably L-methionine) is most preferable. Among the basic amino acids, arginine (preferably L-arginine) can be preferably exemplified. The salt of the amino acid is not particularly limited, but the salt of the basic amino acid may be a hydrochloride, a hydrobromide salt, a bisulfite salt, an acetate salt, a citrate salt, or a carbonate salt. Is most preferred. The inorganic salt is not particularly limited, but is preferably a hydrochloride or sodium salt, and sodium chloride is most preferable. The sugar alcohol is not particularly limited, but for example, Mantol can be exemplified.

As one aspect of the present invention, a liquid composition containing component 1, containing at least one component (component 2) among monosaccharides, disaccharides, amino acids or salts thereof, inorganic salts, sugar alcohols,
A liquid composition having a pH of acidic to neutral (for example, pH 3.0 to 5.0) can be mentioned. The ratio of component 1 to component 2 in such a composition is not particularly limited, but component 1: component 2
It is preferable that the mass ratio is usually 1:0.5 to 50. Further, such a composition preferably further contains an acetate buffer. When sugar alcohol is used as the component 2, the amount of the component 2 relative to the amount of the component 1 is 8 times or less, preferably 5 times or less, and most preferably 3 times or less. it can.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples and can be implemented in any form without departing from the spirit of the present invention.

In addition, in the following examples, "prescription" may be described as a word corresponding to the "liquid pharmaceutical composition" of the present invention.

Example 1 (Preparation of liquid pharmaceutical composition):
(1) Prescriptions 1 to 8:
Formulations 1-8 were prepared according to Table 4 below.

Specific prescription Each preparation method is as follows. First, each additive described in the "additive" column in the table was mixed with water for injection to prepare a solution a in a total amount of 3000 mL. Teriparatide acetate (282 mg as teriparatide) was dissolved in 1600 mL of solution a to prepare a drug solution a.
Was prepared. After that, the diluted hydrochloric acid was added to the drug solution a to adjust the pH to the value shown in the “pH” column in the table, and then a total volume of 2000 mL was prepared using the solution a.

Each formulation was sterilized by filtration and then filled in 2 mL ampoules, 2 mL each, to produce ampoules filled with each formulation (prescription ampoule formulation).
The composition of each formulation is as described in the "final content" column in the table.

(2) Prescription 9:
A commercially available teriparatide preparation (“56.5 μg for subcutaneous injection of teribon” manufactured by Asahi Kasei Pharma Co., Ltd.; Non-Patent Document 1) was added with 0.45 mL of the physiological saline solution of JP, and the resulting drug solution was dissolved by a syringe.
． 2 mL was taken, a formulation 9 was prepared, and a syringe filled with the formulation 9 was used as a formulation 9 formulation. The formulation 9 has a volume of 0.2 mL and contains 28.2 μg of teriparatide acetate in terms of teriparatide as a single dose.

(3) Prescription 10:
Formulation 10 obtained by adding 1.0 mL of physiological saline solution of Japanese Pharmacopoeia to a commercially available teriparatide formulation (“56.5 μg for subcutaneous administration of Teribon” manufactured by Asahi Kasei Pharma Co., Ltd.; The prepared syringe was used as formulation 10 formulation. The formulation 10 has a volume of 0.89 mL and contains 63.5 μg of teriparatide acetate in terms of teriparatide as a single dose.

(4) Prescription 11:
Formulation 11 was prepared according to Table 5 below.

Specific prescription Each preparation method is as follows. First, each additive described in the "Additives" column in the table was mixed with water for injection to prepare a solution a in a total amount of 3000 g. 2480 g of solution a
Was dissolved in teriparatide acetate (352.5 mg as teriparatide), and the total amount was adjusted to 2500 g using solution a to prepare Formulation 11.

After sterilizing the formulation 11 by filtration, 0.2 mL each was filled in a plastic syringe, and the syringe filled with the formulation 11 was used as the formulation 11 formulation.

(5) Prescription 12 to 15:
Formulations 12-15 were prepared according to Table 6 below.

The specific method for preparing each formulation is as follows. First, each additive solution described in the "Additives" column in the table is mixed with water for injection, and the teriparatide acetate solution (2820 μg/mL as teriparatide) in the amount described in the "Teriparatide addition amount" column is added to the mixed solution. Then, about 19 mL of drug solution a
Was prepared. Here, the solvent of each additive solution and the teriparatide acetate solution was used as water for injection. Furthermore, the pH was adjusted to the pH described in the "pH" column in the table by adding the pH adjusting agent described in the "pH adjuster" column in the table to the chemical liquid a to prepare 20 mL of each formulation.

Each formulation was sterilized by filtration and then filled in plastic vials in an amount of 5 mL each to produce a plastic vial filled with each formulation and subjected to a rat pharmacokinetic test.
The composition of each formulation is as described in the "final content" column in the table.

(6) Prescriptions 16 to 23:
Formulations 16-23 were prepared according to Table 7 below.

The specific method for preparing each formulation is as follows. First, each additive solution described in the "Additive solution" column in the table was prepared using water for injection. Teriparatide acetate (91.769 mg as teriparatide) was dissolved in 4.5 mL of the additive solution to prepare a drug solution a. Then, hydrochloric acid was added to the drug solution a to adjust it to the pH described in the “pH” column in the table, and then a total amount of 5 mL of the formulation was prepared using water for injection.

The composition of each formulation is as described in the "final content" column in the table.

(7) Prescription 24 to 30:
Formulations 24-30 were prepared according to Table 8 below.

The specific method for preparing each formulation is as follows. The chemical solutions described in the "Chemical solution a" column and the "Chemical solution b" column in the table were prepared, and the pH thereof was adjusted to 4.1 using hydrochloric acid or sodium hydroxide. Then, each prescription was produced by mixing 2.5 mL of the chemical solution a and 2.5 mL of the chemical solution b.

The composition of each formulation is as described in the "final content" column in the table.

(8) Prescription 31-32:
Formulations 31-32 were prepared according to Table 9 below.
The specific method for preparing each formulation is as follows.

Formulation 31 was prepared by weighing teriparatide described in the “teriparatide” column in the table and adding “additive” in the table.
The teriparatide was dissolved using each additive solution and water for injection described in the column, and then the solution was diluted to 1000 μL with water for injection.

Formulation 32 weighs teriparatide described in the “teriparatide” column in the table, dissolves the teriparatide using 440 μL of each additive solution and water for injection described in the “additive” column,
After adjusting the pH of the dissolved solution according to the description in the “pH adjuster” and “pH” columns in the table, the solution was adjusted to 1000 μL with water for injection.

The composition of each formulation is as described in the "final content" column in the table.

(9) Prescription 33-40:
Formulations 33-40 were prepared according to Table 10 below.

Specific prescription Each preparation method is as follows. First, each additive (however, L-methionine is a pre-dissolved L-methionine solution) described in the "Additives" column in the table is mixed with water for injection to give teriparatide acetate (1425.6 mg as teriparatide). In addition, a total amount of 9.5 kg of the drug solution a was prepared. Then, the diluted hydrochloric acid was added to the drug solution a to adjust it to the pH described in the “pH” column in the table, and then a total amount of 10.10 kg of the formulation was prepared using water for injection.

Each formulation was subjected to filter sterilization treatment, and then filled into ampules in an amount of 2 mL to prepare ampules (formulation formulation) filled with each formulation and subjected to a human pharmacokinetic test. The prescription formulation is
The formulation volume is 0.2 mL, and the formulation is filled with a formulation containing 28.2 μg of teriparatide acetate in terms of teriparatide as a single dose.

The composition of each formulation is as described in the "final content" column in the table.

Example 2 (cation exchange chromatography test by column method):
(1) Test 1:
(1-1) Method:
About 0.8 mL of TOYOPEARL ^{(registered trademark)} SP-650M, which is an anion resin, was collected, and 0.8 mL was collected.
Packed in an empty spin column. After that, the resin was equilibrated with PBS (pH 7.4). Then, each of the above-mentioned prescriptions 12 to 15, prescription 9, and prescription 11 is 0.8 m.
L was added dropwise and the eluate was collected. Then, the operation of dropping 0.8 mL each of PBS (pH 7.4) and collecting the same was repeated. The content of teriparatide contained in each recovered drug solution was measured by HPLC.

(1-2) Result:
The test results are shown in Table 11 below.

Of the total 6 prescriptions, the prescription containing no acetate buffer (prescription 12 and prescription 9 in total 2 prescriptions) was compared with the prescription containing acetic acid buffer (prescription 13 to 15 and prescription 11 total 4 prescriptions). It was found that the elution was rapid in the separation system of (the elution peak time of teriparatide was short).

(2) Test 2:
(2-1) Method:
About 0.8 mL of TOYOPEARL ^{(registered trademark)} SP-650M, which is an anion resin, was collected, and 0.8 mL was collected.
Packed in an empty spin column. After that, the resin was equilibrated with PBS (pH 7.4). Then, 0.4 mL of each of the above Formulations 1 to 8, Formulation 9 and Formulation 11 was dropped, and the eluate was collected. Then, the work of dropping 0.4 mL each of PBS (pH 7.4) and collecting the same was repeated. The content of teriparatide contained in each recovered drug solution was measured by HPLC.

(2-2) Result:
The test results are shown in Table 12 below.

Among the prescriptions 1 to 8, almost the same prescription group (prescriptions 1, 2, 5, 6, 8) as the prescription group found to be more preferable from the viewpoint of pharmacokinetics in the human pharmacokinetic test is It was found that the elution time of teriparatide (teriparatide peak time) was shorter than that of the formulation groups (formulations 3, 4, and 7) that were almost the same as.

Example 3 (Cation exchange chromatography test by batch method (cation exchange resin adsorption
Recovery test)):
(1) Method:
About 0.015 m of TOYOPEARL ^{(registered trademark)} SP-650M which is an anion resin
The resin was collected in an L microtube and washed with PBS (pH 7.4). afterwards,
Each of the formulations 1 to 9 and 11 was added to a 1 mL microtube and suspended in a resin, and then only the supernatant was collected and the recovery rate of teriparatide was measured by HPLC.

(2) Result:
The test results are shown in Table 13 below.

Of the prescriptions 1 to 8, the prescription groups (prescriptions 1, 2, 5, 6, 8) that are almost the same as the prescription groups found to be more preferable in terms of pharmacokinetics in the human pharmacokinetic test are the test subjects Has a teriparatide recovery rate of 80% or more, and is almost the same as the rest of the prescription groups (prescription 3,
When 4, 7) was used as a test object, the teriparatide recovery rate was 40 to less than 80% (more specifically, less than 50%).

Similarly, when the formulation 11 which was not found to be preferable in comparison in terms of pharmacokinetics in the human pharmacokinetic test was used as a test subject, the recovery rate of teriparatide was 40 to less than 80% (
More specifically, it was less than 50%).

Example 4 (Zeta potential measurement test):
(1) Test 1:
(1-1) Method:
A zeta potential evaluation test was performed using each of the above formulations 24 to 32.

Specifically, the zeta potential of the charged particles dispersed in each formulation was measured by an electrophoretic light scattering measurement method known per se. As a measuring device, a dynamic light scattering measuring device (Zetasizer Nano ZS, Malve
rn Instruments Ltd) was used.

(1-2) Result:
The test results are shown in Table 14 below.

The charged particles dispersed in each formulation are considered to be substantially positively charged teriparatide, and the zeta potential, which is the potential of the sliding surface of the charged particles (teriparatide) in the formulation (prescription 24) containing no additive, is 32.2 mV. It has been found that the absolute value of the zeta potential can be lowered by addition of a predetermined additive to the formulation.

(2) Test 2:
(2-1) Method:
A zeta potential evaluation test was performed using the above-mentioned formulations 16 to 23. Specifically, the zeta potential of the charged particles dispersed in each formulation was measured by an electrophoretic light scattering measurement method known per se. A dynamic light scattering measurement device (Zetasizer Nano ZS, Malvern Instruments Ltd) was used as a measurement device.

(2-2) Result:
The test results are shown in Table 15 below.

Example 5 (human pharmacokinetic study):
(1) Human pharmacokinetic study (1):
(1-1) Method:
A human pharmacokinetic test (1) was carried out using the formulations 10 to 11 described above.

Specifically, a pharmacokinetic study was conducted in 12 open-ended healthy postmenopausal women and prescription 1
The pharmacokinetic parameters of a single subcutaneous administration of 0 in the abdomen were compared to the formulation 11 administered subcutaneously in the upper arm.

Plasma teriparatide concentration was 1,1.5 before, 5, 15, 30, 45 minutes after administration.
The measurement was performed on blood samples collected after 2, 3, 4, 6 hours. From the plasma teriparatide concentration,
Pharmacokinetic parameters AUC _last , AUC _inf and C
_max was calculated for each subject.

AUC _last = linear trapezoidal method plasma concentration of up to (linear trapezoidal rule) by the final observation time - area under the curve _{(AUC last} even identical definition in human pharmacokinetic studies Test (2))
AUC _inf = linear trapezoidal method plasma concentration of up to (linear trapezoidal rule) according infinity time - area under the curve _{(AUC inf} also identical definition in human pharmacokinetic studies Test (2))
C _max = maximum plasma concentration _{(C max} also identical definition in human pharmacokinetic studies Test (2))

For the calculated AUC _last , AUC _inf and C _max , the ratio of the prescription 11 to the prescription 10 and the 95% confidence interval were calculated by the following method. Log-transformed AUC _last , A
Regarding UC _inf and C _max , subjects (within the ordinal group) were set as random effects, and the ordinal groups and preparations (formulations 10 to 11 preparations) were set as fixed effects. The estimated drug product difference and the 95% confidence interval were index-transformed and presented in the form of ratio and confidence interval for each formulation.

(1-2) Result:
The test results are shown in Table 16 below.

(2) Human pharmacokinetic study (2):
(2-1) Method:
A human pharmacokinetic study (2) was carried out using each of the above-mentioned formulations 33 to 40 and formulation 10.

The subjects were 24 healthy postmenopausal women. The study was carried out in an open-label manner by comparing the pharmacokinetic parameters obtained by single subcutaneous administration of formulations 33-40 to the abdomen with the pharmacokinetic parameters obtained by subcutaneous administration of formulation 10 to the upper arm. ,Carried out.

This test was conducted in two cohorts, the I, II, III, and IV groups being cohort 1 and the V, VI, VII, and VIII groups being cohort 2. For each cohort, 12 were randomly assigned to 3 groups of 4 each.
The subjects were administered Formulations 33-40 and Formulation 10 according to the dosing schedule shown in Table 17 below.

In Table 17 below, "-" means the fact that none of the prescriptions 33 to 40 and the prescription 10 were administered. It was administered once in each phase, and the number of days in each phase was set appropriately according to the purpose of this study.

Plasma teriparatide concentrations were 1, 1.5, 2 before, 15, 30, and 45 minutes after prescription administration.
It was measured using blood samples taken after 3, 4, and 6 hours. The pharmacokinetic parameters AUC _last , AUC _inf, and C _max were calculated for each subject from the plasma teriparatide concentration by a method not depending on the model.

Formulation 10 to Formulation 3 for the calculated AUC _last , AUC _inf, and C _max
Ratios of 3-40 and 95% confidence intervals were calculated by the following method. First, the calculated AUC _last
, AUC _inf and C _max are log-transformed and then log-transformed AUC _last , AU
With respect to C _inf and C _max , the subjects (within the ordinal group) were set as random effects, and the ordinal groups and the prescriptions were set as fixed effects. The estimated difference between each prescription and the 95% confidence interval were subjected to exponential conversion, and shown in the form of the ratio and confidence interval of each prescription.

Furthermore, AUC _inf (11.4 ng·min/mL) obtained by performing another human pharmacokinetic test using a teriparatide formulation different from the formulations 33 to 40, and the above formulation 33
The absolute bioavailability (%) of teriparatide in plasma was estimated using the AUC _inf calculated in -40 according to the following mathematical formula 1.

(2-2) Result:
The test results are shown in Tables 18 and 19 below.

Example 6 (rat pharmacokinetic study):
(1) Method:
Rat pharmacokinetic studies were performed using each of the above formulations 12-15.

Each of the prescriptions 12 to 15 was administered to 8 week-old male SD rats (Japan SLC) with 28 prescriptions.
． Subcutaneous administration was performed at a dose of 2 μg/head, and blood was collected from the subclavian vein at 5, 15, 30, 60, 120, 180 minutes after administration, or 5, 15, 30, 45, 60, 90 minutes after administration. .. The PK test was divided into 5 tests (Tests 1 to 5). Two to five animals were used in each test.

Plasma was collected from the blood obtained by these blood collections by centrifugation, and the teriparatide concentration in the plasma was measured by ELISA (High Sensitivity Human PTH(1-34) ELISA kit, Immutopics).
Inc.). The area under the plasma concentration-time curve (AUC) was calculated based on the plasma teriparatide concentration obtained by the measurement.

(2) Result:
The test results are shown in Table 20 below.

According to each method of the present invention, a good liquid composition containing a medicinal component can be economically designed or developed. The present invention is extremely useful in the pharmaceutical industry.

Claims (5)

A liquid pharmaceutical composition comprising teriparatide acetate (component 1), and one or more components (component 2) selected from the group consisting of methionine, sodium chloride, arginine or a salt thereof, and sucrose, A liquid pharmaceutical composition having a pH of 4.1 to 5.0 and a component 1 content per administration of 28.2 μg in terms of teriparatide. The liquid pharmaceutical composition according to claim 1, which contains methionine and sodium chloride as Component 2. The liquid pharmaceutical composition according to claim 1, which comprises methionine and sucrose as component 2. The liquid pharmaceutical composition according to claim 1, comprising sodium chloride and sucrose as component 2. The liquid pharmaceutical composition according to claim 1, further comprising mannitol.